This invention relates generally to novel Atomic Force Microscope (AFM) tips and methods of using the novel AFM tips. In particular the present invention relates to arrays of AFM tips and methods and systems for manufacturing the same.
Modern scientific devices include technology which use extremely sharp tips and low forces to characterize the surface of a sample. In some cases, the characterization can be accomplished at atomic dimensions in which cases scanning probe microscopes (SPMs), such as the atomic force microscope (AFM), are used. Generally, the tip of AFM probe is introduced to the sample surface to detect changes in the characteristics of the sample. Automated processes track relative scanning movement between the tip and the sample, surface characteristic data are thereby acquired over a particular region of the sample and a corresponding map of that region of the sample is generated on a computer simulation.
An AFM microscope typically scans the tip, while keeping the force of the tip on the surface of the sample generally constant. This is accomplished by moving either the sample or the probe assembly up and down generally perpendicularly to the surface of the sample in response to a deflection of a cantilever included in the probe assembly as the probe is scanned across the surface of the sample. Data thereby generated from the vertical motion can be stored in data processing apparatus and then used to construct a simulated image of the surface of the sample.
In some specific measurement methods, a tip is oscillated at or near a resonant frequency of the associated cantilever of the probe. The amplitude or phase of this oscillation is kept constant during scanning using feedback signals, which are generated in response to tip-sample interaction. Feedback signals can collected by automated data processing techniques, and stored thereby representing a characterization of the sample.
The deflection of the cantilever in response to the probe tip's interaction with the sample is measured with a deflection detector, such as an optical lever system. In such optical systems, a lens can be employed to focus a laser beam, from a source typically placed overhead of the cantilever, onto the back side of the cantilever. A reflective portion fixed to the lever such that a beam may be reflected from the reflective portion towards a photodetector. The translation of the beam across the photodetector during operation can thereby provide a measure of the deflection of the lever, and, therefore also provide a simulation of one the sample. In some instances, an AFM probe tip can also be modified with a ligand of interest prior to the scan.
However, as effective as the AFM techniques may be, the process is generally tedious and heretofore it has been very difficult, if not essentially impossible, to exactly replicate a condition under which a first scan has been performed a first ligand and a subsequent scan performed with a different ligand. In some instances, it may be possible to utilize a midstream probe switch, however this process is very complicated and difficult to precisely replicate.
According to some studies, the average cost of bringing a drug from pencil and paper through FDA approval may be as high as $800 million and take about 15 years. A significant portion of this time and money can be spent identifying suitable drug candidates, wherein many drug candidates are tested and explored utilizing, amongst other tests, the AFM techniques described above, but eventually abandoned.
Therefore it would be useful to have a development process and technology, wherein researchers may streamline research and development via advanced structural and chemical analysis of biological samples and in particular, proteins. Such a development process and technology would not only be useful to allow for the more rapid development and testing of promising compounds, but may also be useful to rule out compounds which are inappropriate, much faster than is currently possible.